Several risk factors for bowel perforation have been identified in clinical trials and case reports (
Figure 1). Some of the most frequently reported established risks for perforation include history of bowel surgery, ulcers, and certain types of cancer.
Evidence has shown that peptic ulcers may be a clinically significant risk factor for perforation.
15 Bevacizumab is associated with ulcers through its inhibition of VEGF. In a Dutch Colorectal Cancer Group phase III study with 755 patients (oxaliplatin, capecitabine, and bevacizumab vs the same regimen with the addition of cetuximab), Tol et al
15 reported 12 patients who had bowel perforation and 4 patients who had gastric ulcers and bowel perforation. The authors recommended using endoscopic evaluation to screen patients receiving bevacizumab for potential ulcers, as they may have the potential to produce lesions that can lead to perforation. Although NSAIDs and steroids have been associated with peptic ulcer disease, whether the risk of peptic ulcers adds to the risk off bowel perforation when combined with steroids or NSAIDs remains to be assessed in future trials.
Certain types of cancer may also be risk factors for bowel perforation. Results of trials have reported bowel perforation rates as high as 8% in patients being treated for pancreatic tumor
20 and as high as 15.4% in patients being treated for ovarian primary tumors,
6 compared with rates of less than 2.5% in other trials.
15,2 The ORBIT trial,
21 which sought to evaluate bevacizumab for ovarian cancer, was closed early after 5 of 44 treated patients developed bowel perforations. All of the patients had platinum-resistant disease and bowel metastasis. In addition, it has been postulated that erlotinib, a drug for the treatment of locally advanced or metastatic non-small cell lung cancer, may interact with bevacizumab to cause perforation.
22 However, only 1 case of bowel perforation associated with both drugs has been reported in the medical literature.
22 In that case report, non-small cell lung cancer had metastasized to the bowel, which could have contributed to the weakening of the bowel wall.
10 The stage of disease and number of prior chemotherapy treatments may be a factor in perforation risk.
18
Surgery may also increase the risk of bowel perforation. Several cases
15 of reported perforation occurred years after surgery and at the site of anastomosis, which may be because of incompletely healed bowel. Other potential risk factors for bowel perforation, like the increased number of pretreatments (ie, chemotherapy), have not shown a clear relationship.
3 A high rate of perforation occurred when bevacizumab was used after surgery in patients with pancreatic cancer.
15
With careful patient screening and selection, future trials may report lower rates of bevacizumab-associated bowel perforation.